Percutaneous absorbents have heretofore been known in various forms including ointment (creams, gels), solid plaster agents, tape agents, cataplasm agents, liniment agents, lotion agents, aerosol agents, etc. For local application, various drugs can be delivered by means of such percutaneous absorbents, including (1) antihistamines, steriods, non-steroid series anti-inflammatory agents, antipruritics, (2) medicines for suppurative skin diseases or for parasitic skin diseases, such as sulfa drugs, antibiotics, etc., (3) other pharmaceutical substances such as skin-softening agents, medicines for leukoplakia vulgaris, etc.
Recently, the transdermal therapeutic system (TTS) has been studied extensively, using preparations for general systemic application, in order to improve the therapeutic effect by maintaining the concentration of a drug in the blood-stream for a long period of time, reducing any harmful side effects occurring due to the pathway of the drug administered, and improving the compliance of drugs. Various kinds of preparations of this type have recently been developed, including nitroglycerin, isosorbitol nitrate, clonidine, scopolamine, etc.
More recently, attention has turned to transdermal systems for medicines that require the controlled release of an active component having a high activity even in a slight amount, poor stability in vivo, and a narrow safety margin (for example, digoxin, lidocaine, quinidine, theophylline, etc.), as drugs for percutaneous administration, are being investigated in this technical field.
Heretofore, natural rubber series substances, synthetic rubber series substances, acrylic resin series substances, celluloses, polysaccharides, silicones or oily gels containing synthetic rubber-mineral oil, etc., as well as sodium acrylate or aqueous gels containing a water-soluble polymer (e.g., polyvinyl alcohol, etc.) and water have been utilized as base substances for drugs for percutaneous administration.
These polymer compounds are used in the base component or additives for a drug for percutaneous administration, either as constitutional components having physical and mechanical characteristics such as self-restorativity, adhesiveness, etc., in the form of a support for a pharmaceutical substance, or as functional components. Such functional component are typically polymers selected on account of the chemical characteristics of the monomer units themselves, chemical characteristics of the segment units of the chain structure and of the main chain and side chains of the polymer units, as well as the chemical interaction between the polymers themselves or the interaction between the polymer and the pharmaceutical component, additionally in the form of an aggregate of the polymer molecules
In most embodiments of conventional percutaneous preparations, polymers are used essentially as constitutional components. Specifically, most polymers are used as a matrix for a drug to be transdermically absorbed, in conventional drug for percutaneous administration. Systems that are designed chiefly on the basis of functional components, in consideration of the interaction between the molecular structure of a polymer and a low molecular compound (drug), have not been as thoroughly investigated in the past. The present invention has been accomplished by molecular-planning of a base component which is extremely useful as a percutaneous absorbent. Polymeric agents capable of producing sustained release of a substance having high physiological activity are few. Japanese Patent Publication No. 9922/86 (corresponding to U.S. Pat. Nos. 4,202,880 and 4,235,988, British Patent No. 1,551,620, and Belgian Patent No. 861,788) relates to the combination of a prostaglandin derivative (sodium fluprostenol) as a substance having high physiological activity and a hydrophilic linear polyoxyalkylene/polyurethane block copolymer as a base component. However, this preparation has the disadvantage that the base component is not heat-sensitive. Japanese Patent Publication No. 9922/86 relates to agents for percutaneous administration and does not disclose an adhesive for percutaneous administration. The base component used in Japanese Patent Publication No. 9922/86 is composed of a block copolymer comprising a repeating unit of ABABAB . . , wherein A represents a hydrophilic part such as one or more polyoxyalkylene and B represents a hydrophobic part such as a diisocyanate and one or more hydroxy compound In addition, Japanese Patent Publication No. 9922/86 teaches that the polymer is dissolved in a solvent and the pharmaceutical substance is admixed and dispersed therein, and when the agent is used, a humor penetrates into the dispersion composition in order to form a diffusing pathway through the body tissue which is kept in contact with the dispersion composition, and as a result, a durable release of the physiological active substance from the agent into the body tissue is attained through the diffusing pathway. Japanese Patent Publication No. 9922/86 discloses a polymer having both hydrophilic and hydrophobic parts, but fails to teach or suggest the importance of the interaction between the polymer and the pharmaceutical substance or the particular relation necessary to permit percutaneous administration on the basis of the molecular planning of the polymer molecules. That is, the polyoxyalkylene constructing the hydrophilic part in Japanese Patent Publication No. 9922/86 cannot be merely simplified as a hydrophilic compound. In practice, from the viewpoint of a molecular structure, the degree of the hydrophilicity or hydrophobicity varies depending upon a ratio of the number of methylene group in the alkylene group and the ether-oxygen or a molecular weight. In case the proportion of the methylene group is high, it becomes practically water-insoluble hydrophobic or lipophilic compound Therefore, Japanese Patent Publication No. 9922/86 does not include an universal principle control release of drugs.
On the other hand, in accordance with the present invention, as described hereinafter, the polyoxyalkylenes are orderly arranged, and the molecular-planning of a hydro-philicity-hydrophobicity tapered polymer and the controlled release of a drug are carried out in consideration of the controlling of the interaction in molecular level between a drug and a polymer.
Recently, mixture systems of pharmaceutical substance/polymer have been extensively studied not only with respect to the pharmacological element but also from the standpoint of the technical field of polymer science. Under the circumstances, the development of polymers which are specifically usable for determined drugs and of the principle of the release of the drug component on the basis of the function of the specific polymers is of course necessary. Moreover, the development of a universal controlled release system, using polymers having a molecular structure that can be changed precisely and strictly in accordance with pharmaceutical substances is earnestly desired.
Most of the above-mentioned conventional base substances which have heretofore been widely used are found in systems that a pharmaceutical component is merely carried by an adhesive agent, and the release of the pharmaceutical component as blended and dispersed in the adhesive agent is extremely poor. In addition, when the adhesiveness of the adhesive component in the system becomes insufficient because of a sweat component or the like, even the pharmaceutical substance present near the surface of the adhesive component cannot adequately penetrate the skin, and therefore, the pharmaceutical effect is likely to be insufficient. Although oily gels or aqueous gels are somewhat better than agents of the above-mentioned type with respect to the release of pharmaceutical components, they reduce the stability of pharmaceutical components. In addition, these preparations have poor retention of shape, when they are in the form of a thin films, and are inadequate with respect to solubility and dispersibility of pharmaceutical substances.
The study which has heretofore been developed on drugs for percutaneous administration roughly classifies one process from the diffusion of a pharmaceutical component in the preparations to the release thereof to a stratum corneum tissue and another process to the distribution of the pharmaceutical component into the stratum corneum tissue and the diffusion of the component into the epidermis, dermis and sub-dermis tissue Drugs for percutaneous administration fail to meet the requirements of either process and cannot be put in practical use.
One condition for an ideal system of a percutaneous administration of a drug is, first of all, that the pharmaceutical component is dissolved and dispersed in a base component as uniformly as possible. However, an excessively high solubility, where the base component and the pharmaceutical component are relatively strongly bonded state and the pharmaceutical component has a low active coefficient is unfavorable, since the rate of release of the pharmaceutical component is undesirably lowered. It is rather desired that the affinity between the pharmaceutical component and the base component be relatively low and that the pharmaceutical component have a high active coefficient, in order to enhance its smooth release. However, an insufficient affinity between the pharmaceutical component and the base component must also be avoided, since the free movement of the pharmaceutical component in the base component during storage of the percutaneous preparations may concentrate the pharmaceutical component in the surface part of an adhesive or permit the pharmaceutical component to bleed out of the adhesive. If so, an expensive drug will be lost, and the release of the pharmaceutical component from the adhesive, immediately after its application to the skin cannot be controlled efficiently. Accordingly, it is desirable that the base component and the pharmaceutical component be in the form of a uniform molecular dispersion where the two components are strongly bonded together or in a similar form thereto during storage, and that the bonded state between the two may be relaxed when the adhesives are applied. When a drug can be uniformly dissolved in a base substance which has a low affinity therewith and had a minimum solubility, the degree of the release of the drug will be elevated, which is economical. Other systems are being investigated, in which a drug is not dissolved in a base substance but is uniformly dispersed therein. One is a matrix-type drug delivery system, which may be a micro-seal type or a microreservoir type. In the former type, a drug which is generally liquid is dispersed in a polymer matrix in the form of a mixture with a powdery material to form a dispersion of micro-spheres. In the latter type, a co-solvent mixture comprising a drug and a liquid material is dispersed in a polymer matrix in the form of a micro-reservoir. In an emulsion-type base component where liquid particles are dispersed in a liquid material, it is considered advantageous to incorporate a fat-soluble drug in the oil phase which is a continuous phase of the W/O-type base component. In another instance, a W/O/W-type composite emulsion has been investigated as an emulsion-type base component of high sealability In spite of various studies as mentioned above, it has not been possible to discover an effective means which can consistently ensure a drug-release of high efficiency, although some improvement of the efficiency of the drug-release has been attained to a limited extent.
Drugs, whether conventionally taken by injection or oral administration, or novel drugs, are required to be administered through a pertinently selected administration pathway in accordance with the property of the drugs themselves, their pharmaceutical effect and their therapeutic object. A percutaneous administration has been employed to attain a local effect in the past, but recently, increasing attention is being paid to the use of such preparations for general systemic application. The variety of drugs which may be used by percutaneous administration has increased, and accordingly, the development of universal base components which can be used for various kinds of drugs of a broad range as well as permitting their sustained release is eagerly sought.